There is evidence that the pathophysiology of depression and anxiety disorders is related to some type of serotonin dysfunction. The tricyclic antidepressant imipramine binds with high affinity to a recognition site associated with the transport of 5-HT. The site at which these trycyclic antidepressants bind is not identical to the 5-HT binding site and yet binding of compounds of this type inhibits the uptake of 5-HT (serotonin); an allosteric relationship is postulated (Charney, D. S., Krystal, J. H., Delgado, P. L., Heninger, G. R., Annu. Rev. Med. 1990, 41: 437). A number of compounds which demonstrate highly selective serotonin uptake inhibition have shown clinical efficacy as antidepressants (Fuller, R. W., Wong, D. T., Ann. N.Y. Acad. Sci., 1990, 600: 68). It has been found that serotonin uptake inhibitors bind with less affinity to neurotransmitter receptors than the tricyclic antidepressants; this lower binding affinity is thought to be responsible for fewer chlorinergic and histaminergic side effects for these uptake inhibitors (Robertson, D. W., Fuller, R. W., Ann. Rep. Med. Chem., 1991, 26: 23) relative to the tricyclic antidepressants.
Serotonin uptake inhibitors are thought to offer clinical advantages over the tricyclic antidepressants because they exhibit fewer severe adverse drug reactions, particularly as far as cardiovascular side effects and overdose potential. Serotonin uptake inhibitors have shown some indications of efficacy in the treatment of obsessive compulsive disorder (Zak, J., Miller, J., Sheehan, D., Fanous, B., J. Clin. Psychiatry, 1990, 49: 23), panic disorders (Balon, R., Pohl, R. I., Yergani, V., Rainey, J., Oxenkrug, G., Acta. Psychiatr. Scand., 1987, 75: 315), alcoholism (Gill, K., Amit, Z., Koe, K., Alcohol, 1988, 349), and feeding disorders (Wong, D., Fuller, R., Int. J. Obesity, 1987, 11: 125). Some of the emotional aspects of Alzheimer's disease were ameliorated by the use of a serotonin uptake inhibitor (Karlsson, I., Clinical Neuropharmacol., 1990, 13 (Suppl 2): 99). There is some indication that the serotonin uptake inhibitor Fluoxetine is effective in the treatment of hypochondriasis (Viswanathan, R., Paradis, C., Am. J. Psychiatr., 1991, 148: 1090).
The adrenergic nervous system plays a major role in the innervation of heart, blood vessel and smooth muscle tissue. Compounds capable of interacting with receptor sites within the adrenergic nervous system can initiate a variety of physiological responses, including vasoconstriction, vasodilation, and increased or decreased heart rate (chronotropic), contactility (inotropic) and metabolic activity. In the past, various adrenergic compounds have been employed to affect these and other physiological responses. However, many adrenergic compounds do not possess significant selectivity to enable desirable interactions with adrenergic receptor sites. That is, these adrenergic compounds do not demonstrate a high degree of specificity for differing receptors types within the adrenergic nervous system in order to obtain a desired physiological response separate from other possible, and perhaps less desirable, responses of the system.
The fact that adrenergic and serotonergic nerve terminals exist in close proximity in various brain regions might indicate some kind of functional interaction between these two neurotransmitter systems. There is evidence that presynaptic alpha-2 adrenergic receptors are located on 5-HT nerve terminals where they function to inhibit the release of 5-HT (Gothert, M., Huth, H., Naunyn-Schmiedegerg's Arch. Pharmacol., 1980, 313: 21 and Gothert, M., Huth, H., Schlicker, E., Naunyn-Schmiedeberg's Arch. Pharmacol., 1981, 317: 199). It has been demonstrated in in vitro slice preparations that alpha-2 antagonists are capable of reversing the inhibition of 5-HT release upon electrical stimulation under quasi physiological conditions by either exogenously applied alpha-2 agonists or endogenous norepineprine (NE) (Charney, D. S., Krystal, J. H., Delgado, P. L. Heninger, G. R., Annu. Rev. Med. 1990, 41: 437). One might therefore conclude that an agent which combines alpha-2 antagonist activity with 5-HT uptake inhibitory activity would be more effective than either activity alone in increasing the biophase concentration of 5-HT. Compounds such as napamezole, Win 51181- 2, which is a potent and selective alpha-2 adrenergic receptor antagonist and also inhibits serotonin (5-hydroxytryptamine, 5-HT) uptake, is under development by Sterling Drug as an antidepressant (Pharma Projects, May 1991, 12). Chromic uptake blockade will, over time, result in down-regulation of the alpha-2 receptor, and perhaps the delay in onset of antidepressant efficacy correlates with the time required for receptor down-regulation.
1-Aminomethyl-1,2,3,4-tetrahydronaphthalenes have been described by J. F. DeBernardis, R. E. Zelle and F. Z. Basha in International Patent Application Number WO 89/06645. One of their generic structures encompasses methylenedioxy and ethylenedioxy heterocyclic compounds which are excluded from the present invention. Their compounds do not possess the selective alpha-2 antagonist activity with the inhibition of serotonin uptake profile of the present compounds.